IBIS: A single-centre, phase II study to evaluate the safety, tolerability and pharmacokinetics of 2-IminoBiotin in acute Ischemic Stroke due to large vessel occlusion

Acute Ischemic Stroke (AIS) is the second leading cause of death after coronary
artery disease globally. In about 30% of cases, AIS is due to large vessel
occlusion (LVO), which can be treated with intravascular therapy (IVT) with
recombinant tissue plasminogen activator (rTPH) such as Alteplase® and
endovascular therapy (EVT) using thrombectomy. Administration of
neuroprotective drugs is a promising new therapy that could slow ischemic core
growth and limit brain cell injury in AIS due to LVO after successful
recanalization and reoxygenation with EVT. In preclinical experiments,
2-iminobiotin (2-IB) has been shown to reduce brain cell injury after
hypoxia-ischemia. In clinical trials in neonates after birth asphyxia and
adults after cardiac arrest, 2-IB has shown no safety issues. Before embarking
on a large study with efficacy as a primary endpoint, safety, tolerability and
pharmacokinetics of 2-IB treatment need to be established in patients with AIS
due to LVO, treated with IVT and/or EVT . Especially, the safety of the
combined administration of 2-IB with Alteplase® needs to be investigated

This study will be a prospective, placebo controlled, randomised phase 2 single
centre study with the primary objective to evaluate the safety and tolerability
of 2-IB when administered to patients with AIS due to LVO, treated with IVT
and/or EVT. The secondary objective will be to study tolerance, feasibility,
pharmacokinetics and preliminary efficacy. Furthermore we will investigate the
optimal timing of administration of 2-IB (as soon as possible after arrival at
the emergency department or after reperfusion treatment).

This study is designed as a randomised controlled phase 2 safety study. The
study population will consist of adults (age >= 18 years for males and age >49
for female patients) with AIS due to LVO. This study will consist of 3
subgroups: patient treated with 2-IB at the start of diagnosis (n=16), and two
groups of patients treated with 2-IB upon successful reperfusion (2x n=10).
Subjects will all receive 2-IB on top of standard treatment. Subgroup analyses
will be performed based on concomitant treatment with IVT. This is an
explorative study, therefore it will primarily focus on safety, tolerability
and pharmacokinetics of 2-IB, using an adaptive design.

Overview of the 3 groups
Group 1 (n=16) Start 2-IB directly at diagnosis of AIS due to LVO
Group 2a (n=10) Start 2-IB at successful reperfusion during EVT for AIS due to
LVO (intravenous bolus administration)
Group 2b (n=10) Start 2-IB at successful reperfusion during EVT for AIS due to
LVO (intraarterial administration)

Randomisation: patients will be randomised between placebo and 2-IB and
subsequently included in an alternating fashion between the 3 groups, divided
between group 1 (treatment upon diagnosis) and group 2a/b (treatment after
successful reperfusion). Patients allocated to treatment upon reperfusion will
be treated with IV (n=10) or IA (n=10) administration of the initial bolus of
study drug. Inclusion will continue until at least 10 patients treated with IVT
are present in group 1 and 2, in order to be able to check for possible
side-effects on the combined treatment of 2-IB with alteplase.

Dose justification: as 2-IB is renally excreted, the dose will be corrected
eGFR at admission, based on pharmacokinetics and safety of 2-IB in a phase II,
open-label, dose-escalation intervention study in adult human patients after
cardiac arrest. Using this dosing scheme targeted AUC could be predicted more
precisely and was tolerated well without drug-related adverse events.

For the assessment of safety and tolerability, vital signs, including heart
frequency and blood pressure and oxygen saturation (pulse oximeter) will be
monitored before and until 15 minutes after 2-IB fixed loading dose
administration. In addition, vital signs will be continuously monitored during
the first 24 hours of hospital admission which is also part of standard care.
Heart rate and blood pressure will be documented at the neurocare unit
according to the following schedule: 0 to 2 hours after admission each 15
minutes, 2 to 8 hours after admission each 30 minutes, 8 to 24 hours after
admission each 60 minutes, body temperature will be documented 0-24 hours each
6 hours. Any change in the vital parameters which leads to an intervention will
also be documented. Routine biochemistry and hematology will be done before the
start of treatment and after the last dose according to clinical protocol. For
the assessment of pharmacokinetics, 4 plasma samples will be collected after
the first loading dose, at 4, 24 hours after the start of 2-IB treatment, and
at 1 and 4 hours after stop of 2-IB infusion (i.e. 25 and 28 hours after start
of 2-IB treatment).
For safety, all subjects will be followed for the duration of their stay in the
hospital and all adverse and serious adverse events will be recorded up to 7
days or until discharge from hospital if this occurs earlier. To gather
preliminary signs of short-term efficacy we will evaluate the levels of
neurofilaments light at t=0hr, 24h ±2h after first dose of study drug and at
5-7 days, or at discharge if this occurs earlier. We will also evaluate levels
of neuron specific enolase (NSE) at 24 hours and 48 hours. In addition to the
primary and secondary outcome parameters, the percentage of patients with
successful vessel recanalization defined as eTICI score grade 2b, 2c and 3
will be recorded. Also the percentage of patients with IVT in each group will
be noted.

The functional outcome for all patients at 3 months after AIS will be collected
as part of standard stroke care, i.e. mortality, modified Rankin Scale score
(mRS, 0 - no symptoms, 6 - death), the Patient-Reported Outcomes Measurement
Information System (PROMIS) and cognitive functioning (as assessed with the
PROMIS short form). PROMIS is a computer adapted test (CAT) measuring a variety
of parameters including physical function, fatigue, anxiety, depression and
pain.

Patients will be included in an alternating fashion between group 1 (treatment
upon diagnosis) and group 2a/b (treatment after successful reperfusion).
Patients allocated to treatment upon reperfusion will be treated in an
alternating fashion with IV (n=10) or IA (n=10) administration of the initial
bolus of study drug. Inclusion will continue until at least 10 patients treated
with IVT are present in group 1 and 2, to test our hypothesis that no
interaction exists between 2IB with Alteplase.

Patient risk is considered moderate (Dutch: matig risico). No specific toxicity
has been demonstrated in preclinical studies and no adverse reactions that
could be attributed to 2-IB have been shown in a Phase I study in adult humans
and a Phase II pilot safety study in newborns with perinatal asphyxia as well
as Phase II study in adult patients with cardiac arrest. Using the NFU
classification, risk may be classified as negligible. Since the patient
population is very vulnerable however, we consider the risk to be "moderate".
The extra burden of participation is limited, since most assessments done are
part of standard clinical care. Study medication and plasma samples will be
administered and obtained through existing intravenous catheters. Monitoring of
vital functions is part of standard care. The dose levels to be given in this
study are derived from effective dose levels in animal models that were
neuroprotective after hypoxia-ischemia, both in newborn and in adult animals,
and similar dose levels were found to be safe in humans investigated with
cardiac arrest (personal communication with PI of TIBOHCA study).